This project will determine whether antagonists of collagen metabolism can ameliorate normal tissue fibrosis induced by ionizing radiation or anti-neoplastic drugs, alone or in combination. The initial target organ is the irradiated lung, and the initial collagen antagonist is D-penicillamine. We have demonstrated that penicillamine reduces radiation injury in rat lung, using structural, biochemical, and functional criteria. These experiments, performed in animals exposed to single doses of gamma rays, are presently being repeated in rats exposed to a fractionated radiation regimen. In addition, we are evaluating the ability of penicillamine to modify lung injury induced by bleomycin, alone and in combination with thoracic irradiation. We also will investigate the effect of other collagen antagonists, and of combinations of anti-inflammatory agents and collagen antagonists, on radiation- and/or bleomycin-induced pulmonary fibrosis. Finally, the ability of penicillamine to modify chronic radiation injury in another critical organ (e.g. kidney, liver, or intestine) will be examined. In total, the funds provided by this grant will enable us to develop a systematic investigation of therapy-related tissue fibrosis, and its possible chemical modification, in organs whose radiation or drug tolerance presently limits the treatment regimen of the oncologist.